US20140039320A1 - Ultrasonic system for assessing tissue substance extraction - Google Patents

Ultrasonic system for assessing tissue substance extraction Download PDF

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US20140039320A1
US20140039320A1 US14/008,500 US201214008500A US2014039320A1 US 20140039320 A1 US20140039320 A1 US 20140039320A1 US 201214008500 A US201214008500 A US 201214008500A US 2014039320 A1 US2014039320 A1 US 2014039320A1
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oxygen
capillary
tissue
blood
ctth
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Sune Nørhøj Jespersen
Kim Mouridsen
Leif Østergaard
Martin Snejbjerg Jensen
Kartheeban Nagenthiraja
Anna Tietze
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Aarhus Universitet
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Aarhus Universitet
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/48—Other medical applications
    • A61B5/4848—Monitoring or testing the effects of treatment, e.g. of medication
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/145—Measuring characteristics of blood in vivo, e.g. gas concentration or pH-value ; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid or cerebral tissue
    • A61B5/14542—Measuring characteristics of blood in vivo, e.g. gas concentration or pH-value ; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid or cerebral tissue for measuring blood gases
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/72—Signal processing specially adapted for physiological signals or for diagnostic purposes
    • A61B5/7271—Specific aspects of physiological measurement analysis
    • A61B5/7282—Event detection, e.g. detecting unique waveforms indicative of a medical condition
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B8/00—Diagnosis using ultrasonic, sonic or infrasonic waves
    • A61B8/06—Measuring blood flow
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B8/00—Diagnosis using ultrasonic, sonic or infrasonic waves
    • A61B8/48—Diagnostic techniques
    • A61B8/481—Diagnostic techniques involving the use of contrast agents, e.g. microbubbles introduced into the bloodstream
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B8/00—Diagnosis using ultrasonic, sonic or infrasonic waves
    • A61B8/48—Diagnostic techniques
    • A61B8/488—Diagnostic techniques involving Doppler signals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B8/00—Diagnosis using ultrasonic, sonic or infrasonic waves
    • A61B8/52—Devices using data or image processing specially adapted for diagnosis using ultrasonic, sonic or infrasonic waves
    • A61B8/5215—Devices using data or image processing specially adapted for diagnosis using ultrasonic, sonic or infrasonic waves involving processing of medical diagnostic data
    • A61B8/5223—Devices using data or image processing specially adapted for diagnosis using ultrasonic, sonic or infrasonic waves involving processing of medical diagnostic data for extracting a diagnostic or physiological parameter from medical diagnostic data
    • G—PHYSICS
    • G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
    • G16H—HEALTHCARE INFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR THE HANDLING OR PROCESSING OF MEDICAL OR HEALTHCARE DATA
    • G16H50/00—ICT specially adapted for medical diagnosis, medical simulation or medical data mining; ICT specially adapted for detecting, monitoring or modelling epidemics or pandemics
    • G16H50/30—ICT specially adapted for medical diagnosis, medical simulation or medical data mining; ICT specially adapted for detecting, monitoring or modelling epidemics or pandemics for calculating health indices; for individual health risk assessment
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B8/00—Diagnosis using ultrasonic, sonic or infrasonic waves
    • A61B8/08—Clinical applications
    • A61B8/0808—Clinical applications for diagnosis of the brain
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B8/00—Diagnosis using ultrasonic, sonic or infrasonic waves
    • A61B8/08—Clinical applications
    • A61B8/0891—Clinical applications for diagnosis of blood vessels

Definitions

  • the present invention relates to an ultrasonic system for measuring a micro-vascular flow distribution of a tissue portion of a mammal.
  • the present invention relates to an ultrasonic system capable of assessing tissue substance extraction transported by the blood, such as oxygen, drugs and nutrients into the tissue.
  • the invention also relates to a corresponding use of an ultrasonic system, a corresponding database, and a corresponding computer program product.
  • perfusion The process of blood entering the tissues is called perfusion, and is one of the most fundamental physiological parameters. Disorders of perfusion is a process leading to mammal disability and mortality.
  • CEU contrast-enhanced ultrasound
  • Angiopathy is the generic term for a disease of the blood vessels, and is further categorized in macroangiopathy and microangiopathy.
  • macroangiopathy the walls of major vessels undergo changes, and ultimately hinder sufficient blood flow.
  • microangiopathy the walls of the smaller blood vessels become so thick and weak that they bleed, leak protein, and slow the flow of blood through the smallest blood vessels, resulting in an impairment of the flow of oxygen and nutrients to the tissues.
  • one aspect of the present invention relates to an ultrasonic system for measuring a micro-vascular flow distribution of a tissue portion of a mammal; the system comprising:
  • Another aspect of the present invention relates to a database comprising references levels of one, or more, of the first indicator, the second indicator and the extraction capacity for one or more subjects with:
  • FIG. 1 shows the metabolic effects of tissue reperfusion in case of reversible and irreversible capillary flow disturbances
  • FIG. 2 shows the metabolic effects of functional hyperemia in case of microvascular flow disturbances owing to basement membrane thickening or changes in pericyte morphology
  • FIG. 3 shows a table with data from all available in vivo recordings, in which transit time characteristics were reported in such a manner that the inventors' model could be applied with limited assumptions. These were all performed in rat brain,
  • FIG. 4 shows the effects of CTTH on oxygen extraction
  • FIG. 5 shows the effects of tissue oxygen tension on the MTT-OEC relation
  • FIG. 6 shows a general model of the effects of vasodilation (x-axis) and CTTH (y-axis) on oxygen extraction capacity.
  • Contour plot of OEC ( 6 . a ) for a given mean transit time ( ⁇ ) and capillary flow heterogeneity ( ⁇ ). The corresponding maximum oxygen delivery is shown in FIG. 6 . b assuming fixed CBV 1.6%, and Grubb's relation in FIG. 6 . c .
  • the effective permeability surface area normalized to the control state is given as a function of ⁇ and ⁇ (Stefanovic et al., 2008).
  • FIG. 7 shows comparison of gold-standard PET OEF and MRI OEC maps
  • FIG. 8 shows oxygen extraction capacity as a function of capillary transit time
  • FIG. 9 is a schematic drawing of a capillary showing various elements in the modelling of the extraction capacity
  • FIG. 10 is a schematic drawing with an ultrasonic system for measuring a micro-vascular flow distribution of a tissue portion of a mammal according to the present invention
  • FIG. 11 is another embodiment of an ultrasonic system for measuring a micro-vascular flow distribution of a tissue portion when subjected to the drug or medicine indicated as “X”,
  • FIG. 12 shows an OEC plot of healthy and diabetic patients
  • FIG. 13 shows to tables; Table 1 gives Mini-Mental-State Examination (MMSE) scores for the test persons (AD and control group); Table 2 gives the summary of the ROI (Region Of Interest) analysis,
  • MMSE Mini-Mental-State Examination
  • FIGS. 14 , 15 , and 16 show various receiver operating characteristics curves (AUC R and AUC WB ) versus oMTT/sMTT, pMTT/oMTT, and OEF/oMTT, respectively,
  • FIG. 17 shows contrast enhanced ultrasound (CEU) results from the unaffected hemisphere on an acute stroke patient
  • FIG. 18 shows contrast enhanced ultrasound (CEU) results from the affected hemisphere on an acute stroke patient
  • FIG. 19 shows a flow chart for image pre-processing in contrast enhanced ultrasound (CEU) in embodiment of the present invention
  • FIG. 20 shows an illustrative left parietal lobe in human for contrast enhanced ultrasound (CEU),
  • FIG. 21 shows an experimental setup with a restrained mouse
  • FIG. 22 shows oblique scan plane (left) and a resulting signal intensities (right) in human brain
  • FIG. 23 shows transverse scan plane (left) and a resulting signal intensities (right) in mouse lower abdomen
  • FIG. 24 shows an OEC plot of the central and peripheral part of the mouse tumour
  • FIG. 25 shows a grey curve that represents the maximum amount of oxygen, which can diffuse from a single capillary into the tissue for a given tissue blood flow (mL blood per 100 mL tissue per minute).
  • the curve shape determines three critical characteristics of oxygen diffusion into tissue: 1) the curve slope decreases towards high flow values, making flow increases gradually more. 2) if tissue capillaries—instead of all having equal flows and transit times as assumed by the classical Bohr-Kety-Crone-Renkin (Crone 1963) equation—were split into two equal-size populations with flows f1 and f2, then net tissue blood flow would remain unaffected, but oxygen availability would be reduced by ⁇ M.
  • capillary transit time heterogeneity does affect tissue for a given flow, even without classical capillary recruitment.
  • CTTH capillary transit time heterogeneity
  • FIG. 26 shows the average capillary transit time heterogeneity at rest and during different exercise intensities (25% and 80% handgrip forces). ⁇ P ⁇ 0.02, comparison between rest and 80% handgrip force. *P ⁇ 0.01, comparison between 25% and 80% handgrip force,
  • FIG. 27 shows the average oxygen extraction capacity at rest and during different exercise intensities (25% and 80% handgrip forces). ⁇ P ⁇ 0.001, comparison between rest and 80% handgrip force. *P ⁇ 0.01, comparison between 25% and 80% handgrip force,
  • FIG. 28 shows the residuals of the CTTH(x) ⁇ OEC(y)-relation.
  • CTTH CTTH(x) ⁇ OEC(y)-relation
  • FIG. 29 shows a schematic outline of theoretical relation between cellular metabolic requirements and muscle blood perfusion.
  • Regular physical exercise improves cardiovascular stability through greater utilisation of Frank Starling mechanism. In the long run, this is believed to induce a balanced production of reactive oxygen species (ROS) and antioxidants, possibly reducing the CTTH. Finally, this will improve muscle tissue oxygenation, leading to beneficial hemodynamic-metabolic coupling.
  • ROS reactive oxygen species
  • the potential ability of pericytes to relax during exercise could possess pivotal effects throughout the entire vascular system by securing optimal oxygenation of organs.
  • lack of regular physical exercise could favor several physiological adaptations, which lead to impaired muscle tissue oxygenation, and, similarly, poor glucose extraction, as observed in diseases such as type-two diabetes (e.g. T2DM),
  • T2DM type-two diabetes
  • FIG. 30 shows an illustration of the biphasic nature of the CBF and BOLD changes during the course of the disease
  • FIG. 31 shows the classical, single capillary flow-diffusion relation for oxygen (Crone, 1963) (bottom curve) shows the maximum amount of oxygen which can diffuse from a single capillary into tissue, for a given CBF.
  • the curve shape predicts crucial properties of ‘real’ parallel-coupled capillaries (case B) as opposed to ‘idealized’ single capillaries (case A): Net tissue oxygen availability always decline if capillary flows differ from their mean (the point labeled B is always below the point labeled A, which corresponds to homogenous flows).
  • FIG. 32 shows contour plot of OEC ( 24 . a .) for a given mean transit time and capillary flow heterogeneity ( ⁇ ).
  • the yellow line in 24 . b . separates states in which increasing transit times lead to increasing oxygen extraction from states where increasing transit times lead to decreasing oxygen extraction: Malignant capillary transit time heterogeneity (CTTH).
  • CTTH Malignant capillary transit time heterogeneity
  • FIG. 24 . c shows net oxygenation as a function of tissue oxygen tension and CTTH for fixed CBF (such as in neurovascular dysfunction).
  • an oxygen tension decrease of 5 mmHg supports a CMRO2 increase of roughly 20%, which correspond to the energy requirements of neuronal firing,
  • FIG. 33 shows the changes in CBF and tissue oxygen tension which are necessary to maintain tissue oxygenation over time, according to the extended BKCR model
  • FIG. 34 shows an example of the application of this technique to a patient with AD, and to a somewhat older control-subject
  • FIG. 35 shows the perfusion values in pre-intervention state.
  • the largest circle indicate the ROI in tissue and the smallest circle indicate the AIF.
  • the scan plane is shown,
  • FIG. 36 shows the perfusion values in post-occlusion state.
  • the largest circle indicate the ROI in tissue and the smallest circle indicate the AIF.
  • the scan plane is shown, and
  • FIG. 37 shows the perfusion values in septic shock state.
  • the blue circle indicate the ROI in tissue and the red circle indicate the AIF.
  • the scan plane is shown in the upper right sub-figure.
  • the inventors of the present invention have found that the flow heterogeneity through the capillary bed has a significant influence on the extraction of a substance transported by the blood, such as oxygen, drugs and nutrients. Furthermore, the inventors have developed a system for predicting such extraction.
  • the inventors have found that there may be hypoxia in tissue despite normal blood flow, and that an indicator for the blood flow through a capillary bed and an indicator of heterogeneity of the blood flow in said capillary bed are needed to say for sure.
  • the inventors have proven that the blood flow through a capillary bed and the heterogeneity of the blood flow in said capillary bed in a range of pre-clinical and clinical diseases is disturbed. This may explain why tissue looses its normal function, degenerates or dies in these diseases, despite normal blood flow.
  • one aspect relates to an ultrasonic system for measuring a micro-vascular flow distribution of a tissue portion of a mammal; the system comprising:
  • the model used by the processor applies a variable shift to k ⁇ X-domain enabling averaging over a transit time distribution to be performed from one capillary, k being the rate constant for diffusion of the substance across the capillary, ⁇ being the mean transit time, and x being the fractional distance of the capillary.
  • the present invention relates to ultrasonic methods (also called medical soniography) using sound waves above approximately 20 kHz for imaging/monitoring, particularly suited for perfusion measurements.
  • ultrasonic methods also called medical soniography
  • CEU contrast-enhanced ultrasonic
  • Doppler based techniques include contrast-enhanced ultrasonic (CEU) techniques and Doppler based techniques.
  • CEU is particularly advantageous for implementing the present invention.
  • CEU is a so-called “harmonic imaging” method comprising the emission of a fundamental frequency of sound, and subsequent detection of higher harmonics resulting from non-linearities in the tissue portion being imaged.
  • Various ways of analysing and excluding the fundamental frequency may be filtering, pulse inversion, power modulation, contrast coded harmonics etc. The skilled reader is referred to “Principles of Cerebral Ultrasound Contrast Imaging” by Jeff Powers.
  • the ultrasonic system is a contrast enhanced ultrasound (CEU) system.
  • CEU contrast enhanced ultrasound
  • the skilled reader is referred for example to Digital techniques in echocardiography by Joe Rolandt, Springer, 1987, for more details about perfusion measurement using ultrasonic methods.
  • the present invention may possibly be implemented in any combinations of the above-mentioned ultrasonic techniques.
  • the contrast agent applied in CEU is preferably micro-bubbles.
  • Other contrast agents known to the skilled person may however also readily be applied within the context of the present invention.
  • the contrast agent is untargeted, but targeted contrast agents may also be applied with the present invention.
  • the processor 110 is arranged for estimating the extraction capacity under the condition that the contrast agent being measured upon is being delivered to the tissue portion so as to reduce a convolution between a residue function (R) with the incoming concentration of contrast agent (J) to an integral mathematical operation.
  • a preferably way of delivering the contrast agent is a short bolus that functions as close as possible to a impulse function. This method however has a very high contrast concentration in the first circulatory pass due to the fact that it is diluted in a small volume. This can cause a unlinear relationship between the concentration and intensity in the arterial input and the method also relies on an artery input. In order to work around these limitations an equilibrium of contrast agent can maintained by having a constant replenishment of contrast agent.
  • the contrast agent is being delivering to the tissue with two different time-dependencies, preferably a substantially constant time dependency and a substantially linear time dependency, the contrast agent preferably being micro-bubbles. The method eliminates the need for a arterial input and contrast equilibrium which may be hard to keep.
  • the contrast agent is also microbubbles and may be delivered with a substantially constant level and is then destroyed using a flash function of the ultrasonic system, whereafter the contrast agent concentration is delivered so as to be linearly increasing (or decreasing) again.
  • the contrast agent concentration may be delivered with a time dependency having a pulse function or a step function to simplify or reduce the mathematical operations performed for finding or estimating the extraction capacity.
  • the ultrasound signal can be converted to a local concentration C(t) of injected microbubbles.
  • C(t) concentration of microbubbles j(t)
  • the incoming concentration of microbubbles j(t) can be modulated.
  • the relations between the residue function and probability density function h( ⁇ ) of capillary transit times is incorporated. If R(t) is the residue function, the usual convolution identity should hold:
  • A is the constant of proportionality dependent on the linear relation between ultrasound signal and concentration, as well as CBF.
  • A is the constant of proportionality dependent on the linear relation between ultrasound signal and concentration, as well as CBF.
  • the error is thus related to the weight of transit times larger than the measurement time t.
  • ⁇ 2 2 AJ 1 ⁇ C 1 ⁇ ( t - C 1 / ( 2 ⁇ AJ 1 ) ) - 2 ⁇ C 2 / ( AJ 2 )
  • plasma concentration refers to the amount of a substance present in the portion of the blood called the plasma.
  • extraction capacity refers to the maximal fraction of a substance that can be extracted from arterial blood during a passage of the capillary bed, according to the biophysical model described.
  • the extraction capacity may be affected by physiological states and pre-clinical and clinical disease states.
  • extraction fraction refers to the fraction of a substance that the cells or the tissue is actually extracting from arterial blood during a passage of the capillary bed, according to the biophysical model described. Hence, the extraction fraction will always be lower than or equal to the extraction capacity.
  • EC e.g. OEC
  • EF e.g. OEF
  • the first processor ( 110 ) is arranged for using the first and the second indicator to estimate an extraction fraction (EF) of a substance from the blood in said capillary bed.
  • EF extraction fraction
  • the first processor ( 110 ) is arranged for using the first and the second indicator to estimate an extraction fraction (EF) and/or extraction capacity of a substance from the blood in said capillary bed.
  • said ultrasonic transducer for measuring the first indicator, and the second indicator, and said processor may—in an individual embodiment of the invention—be physically, functionally and logically implemented in any suitable way such as in a single unit, in a plurality of units or as part of separate functional units.
  • the invention may be implemented in a single unit, or be both physically and functionally distributed between different units and processors as will be readily understood by a person skilled in the art.
  • the invention can be implemented by means of hardware, software, firmware or any combination of these.
  • the invention, or some of the features thereof, can also be implemented as software running on one or more data processors and/or digital signal processors.
  • the present invention also relates to a computer program product being adapted to enable a computer system comprising at least one computer having data storage means in connection therewith to control said ultrasonic system according to an aspect of the invention.
  • capillary bed refers to an interweaving network of capillaries supplying a specified part of an organ or a tissue.
  • the capillary bed may, in the context of present invention, have various spatial extensions depending of the nature of the means applied for measuring the first indicator for the blood flow through the capillary bed; and/or the nature of the means for measuring a second indicator of heterogeneity of the blood flow in said capillary bed, and/or on the tissue being measured upon.
  • the capillary bed or structure consists of a network of capillaries having a basic dimension in the micro-meter range; typical brain capillary has for instance a length of 120 micrometer and 8 micrometer in diameter.
  • the extension of the capillary bed will therefore be limited from below by the need for measuring on a plurality of capillaries to derive a meaningful measure of the heterogeneity (CTTH).
  • CTTH heterogeneity
  • the extension of the capillary bed will typically be limited by the available spatial resolution of the ultrasonic measurement means applied for measuring the said first and second indicator as will readily be appreciated by the skilled person working with medical imaging techniques, in particular ultrasonic imaging techniques.
  • Some typical resolutions may be in order of millimetres, e.g. axially 1.1 mm and laterally 2.8, due to the use of contrast agent, e.g. microbubbles.
  • the flow of blood, and the heterogeneity thereof in the capillary bed may therefore be derived from flows measured on various spatial dimensions.
  • the spatial scale may extends beyond many capillaries.
  • every imaging ultrasonic modality has an effective voxel size that should be adapted and/or compensated for when implementing the present invention in practise.
  • ultrasonic techniques applying contrast agents e.g. microbubbles
  • the physical extension of capillary bed may be in the range of 50-2000 micrometer, preferably 100-1000 micrometers, more preferably 200-500 micrometers.
  • total substance concentration refers to the total concentration of the substance of interest in all of its forms present in the blood; e.g. the sum of non-bound substance in the plasma+substance bound to serum protein+substance contained in the blood cells.
  • the processor may apply a model connecting the first (MTT) and the second ( ⁇ ) indicator to the said extraction capacity (EC) of a substance from the blood in said capillary, the model comprising the transfer rate of total substance concentration (C T ) across the capillaries being linearly dependent on the plasma concentration of the substance (C P ).
  • the linear dependence on the plasma concentration of the substance (C P ) of the model may deviate to some extent from the exact linear dependency, e.g. the linear dependency may an initial approximation to a more advanced model having non-linear terms. It is also contemplated that the invention may be implemented in another variant with a more complex behaviour than linear.
  • the model further includes a non-vanishing back flow of the substance from the tissue into the capillaries.
  • the back flow may be non-negligible, or significantly above zero.
  • the first indicator is related to a mean transit time (MTT) of the blood flow through a capillary bed
  • the second indicator is related to the standard deviation ( ⁇ ) of the mean transit time of the blood flow.
  • the first indicator is related to a mean velocity of the blood flow
  • the second indicator is related to the standard deviation ( ⁇ ) of particle velocities in the blood flow.
  • the term “particle” refers to any molecule or amount of molecules (such as a gas bubble) being transported by the blood, or any blood cell, such as a red blood cell.
  • the model is based on at least one rate constant, k, related to the permeability of the capillary wall to the substance.
  • the rate constant, k may describe two directions, i.e., from the capillaries to the tissue and from the tissue to the capillaries.
  • capillary wall refers to the capillary wall comprising endothelial cells, a basement membrane, and surrounding cells called pericytes.
  • the capillary wall may have undergone structural changes or deposits (amyloid etc.).
  • Blood is a specialized bodily fluid that delivers necessary substances to the tissues cells, such as nutrients and oxygen, and transports waste products, excess nutrients and excess oxygen away from e.g. those same cells.
  • blood is composed of blood cells suspended in a liquid called blood plasma.
  • Blood plasma is blood minus the blood cells. It comprises water, dissipated proteins (serum proteins), glucose, mineral ions, hormones and carbon dioxide.
  • the blood cells present in blood are mainly red blood cells (also called RBCs or erythrocytes), white blood cells and platelets.
  • RBCs or erythrocytes red blood cells
  • the most abundant cells in mammal blood are the red blood cell. These contain haemoglobin, an iron-containing protein, which facilitates transportation of oxygen by reversibly binding to this respiratory gas and greatly increasing its solubility in blood.
  • carbon dioxide is almost entirely transported extracellularly dissolved in plasma as bicarbonate ions.
  • the term “substance” refers to any molecule being transported by the blood, such as oxygen, lactate, insulin, nutrients (e.g. glucose), drugs, and signal molecules (e.g. NO, and various hormones).
  • the inventors of the present invention consider first a single capillary (11) of length L and volume V (cf. FIG. 9 ), assuming that the substance inside the capillary is well stirred along the radial direction, and that the current of substance across the capillary wall is proportional to the difference between plasma concentration of the substance (C P ) and tissue concentration of the substance (C t ).
  • the differential equation for total substance concentration C as a function of the fractional distance ⁇ [0, 1] along a capillary with flow f and volume V then reads
  • the inventors are assuming equal forward and reverse rate constants k of the substance across the capillary barrier ( 12 ) for simplicity.
  • the model applied in the present invention may readily be extended to the situation where the forward and reverse rate constants are different from each other. Note that the capillary transit time is identical to V/f.
  • the model applies a variable shift to k ⁇ x-domain enabling averaging over a transit time distribution to be performed from one capillary, k being the rate constant for diffusion of the substance across the capillary, ⁇ being the mean transit time, and x being the fractional distance of the capillary.
  • the oxygen concentration C as a function of fractional distance x along the capillary may be described by the differential equation
  • ⁇ f ⁇ y - ( ⁇ H ⁇ P 50 ⁇ ( f B - f ) 1 / h - C t )
  • h(y/k)/k corresponds to a gamma-variate with parameters ⁇ and k ⁇ .
  • the integral can be carried out analytically, and it is thus easy to compute OEC for any given value of k given a significant advantage upon implementation.
  • C B is the concentration of substance in blood not freely dissolved in plasma, e.g. bound to a plasma protein.
  • C B is the concentration of substance in blood not freely dissolved in plasma, e.g. bound to a plasma protein.
  • the substance is oxygen (O 2 ):
  • the model further includes substance cooperativity due to a non-linear binding of the substance with a protein in the blood.
  • the substance is oxygen and the model includes oxygen cooperativity due to the non-linear binding of oxygen with haemoglobin.
  • the substance is oxygen and the extraction capacity is oxygen extraction capacity (OEC).
  • OEC oxygen extraction capacity
  • ⁇ and ⁇ are related to mean transit time, MTT, and the heterogeneity, ⁇ , by:
  • the substance is glucose and the extraction capacity is glucose extraction capacity.
  • the substance is insulin and the extraction capacity is insulin extraction capacity.
  • the substance is a drug (A):
  • the drug A is freely dissolved in plasma or bound to a plasma protein P as described by the biochemical equilibrium:
  • C p can be expressed in terms of the total concentration C and the protein content given by [P]+[AP].
  • a drug's binds to the proteins within blood plasma (plasma proteins).
  • plasma proteins Common blood proteins that drugs bind to are human serum albumin, lipoprotein, glycoprotein, ⁇ , ⁇ , and ⁇ globulins. This means that there are two populations of molecules, where only the free pool can directly cross the capillary wall. In the creation for the extraction faction, one would thus need a relation between total substance concentration and free substance concentration. This could involve e.g. the Langmuir equation.
  • the concentration of bound drug A is v ⁇ C prot . This can be expressed in terms of C p and C since one has:
  • Binding curves i.e. relating v to x also include other cases readily available to the skilled person, for example the Hasher and von Hippel model where ligands ‘crowd’ each other out as expressed by
  • v k K ⁇ ( 1 - nv ) ⁇ ⁇ 1 - nv 1 - ( n - 1 ) ⁇ v ⁇ ( n - 1 )
  • n is the number of sites occupied by one ligand.
  • Adair equation can then be considered a refined model of oxygen binding with
  • binding polynomial in the MWC Allosteric Model the binding polynomial can be expressed as
  • MRI magnetic resonance imaging
  • CTTH capillary transit time heterogeneity
  • the inventors propose (in a non-limiting manner) the following links between microvascular hemodynamic derangement, and metabolic impairment and death of cells; here exemplified in FIGS. 1 and 2 :
  • FIG. 1 shows the metabolic effects of tissue reperfusion in case of reversible and irreversible capillary flow disturbances.
  • FIG. 1 has been modified such that the CMRO 2 threshold (less than 2.5 mL/100 mL/min) for irreversible tissue damage is highlighted in grey.
  • the perfusion pressure drop cause acute increase in the CBV/CBF ratio.
  • FIG. 2 show the metabolic effects of functional or active hyperemia in case of microvascular flow disturbances owing to basement membrane thickening, endothelial or pericapillary edema or changes in pericyte morphology (cf. microangiopathies in hypertension, diabetes, Alzheimer's Diseases, and in angiogenesis and Moya-moya-disease).
  • Degenerative diseases such as diabetes, chronic hypertension and Alzheimer's Disease cause profound changes in capillary basement membrane thickness, pericyte morphology (Diaz-Flores et al., 2009; Hamilton et al., 2010) and capillary patency (Bell et al., 2010), leading to increase, resting CTTH.
  • angiogenesis cause ‘chaotic’ capillary paths with wide CTTH distributions (Observed so far in Alzheimer's Disease and diabetes).
  • Functional hyperemia or active hyperemia, is the increased blood flow that occurs when tissue is active.
  • Reactive hyperemia is the transient increase in organ blood flow that occurs following a brief period of ischemia.
  • Moya moya syndrome is a disease in which certain arteries in the brain are constricted. Blood flow is blocked by the constriction, and also by blood clots (thrombosis).
  • ischemia refers to a restriction in blood supply, generally due to factors in the blood vessels, with resultant damage or dysfunction of tissue (e.g. myocardial ischemia).
  • the term “circulatory shock” refers to perfusion of tissues which is insufficient to meet cellular metabolic needs. As the blood carries oxygen and nutrients around the body, reduced flow hinders the delivery of these components to the tissues, and can stop the tissues from functioning properly. The process of blood entering the tissues is called perfusion, so when perfusion is not occurring properly this is called a hypoperfusional state or hypoperfusion.
  • hypoxia refers to a condition in which the body as a whole (generalized hypoxia) or a region of the body (tissue hypoxia, e.g. cerebral hypoxia or hypoxia in the heart) is deprived of adequate oxygen supply. Prolonged hypoxia induces cell death via apoptosis resulting in a hypoxic injury.
  • Cerebral hypoxia refers to reduced brain oxygen, and can be classified as follows:
  • hypoxic hypoxia is a situation where limited oxygen in the environment causes reduced brain function. The term also includes oxygen deprivation due to obstructions in the lungs. Choking, strangulation, the crushing of the windpipe all cause this sort of hypoxia. Severe asthmatics may also experience symptoms of hypoxic hypoxia.
  • Hypemic hypoxia is a situation where reduced brain function is caused by inadequate oxygen in the blood despite adequate environmental oxygen. Anemia and carbon monoxide poisoning are common causes of hypemic hypoxia.
  • Ischemic hypoxia also known as stagnant hypoxia
  • Ischemic hypoxia is a situation where reduced brain oxygen is caused by inadequate blood flow to the brain. Stroke, shock, and heart attacks are common causes of ischemic hypoxia. Ischemic hypoxia can also be created by pressure on the brain. Cerebral edema, brain hemorrhages and hydrocephalus exert pressure on brain tissue and impede their absorption of oxygen.
  • Oxygen is present in brain tissue but cannot be metabolized. Cyanide poisoning is a well-known example.
  • stroke refers to the rapidly developing loss of brain function(s) due to disturbance in the blood supply to the brain. This can be due to ischemia (lack of blood flow) caused by blockage (thrombosis, arterial embolism), or a hemorrhage (leakage of blood). As a result, the affected area of the brain is unable to function.
  • Silent stroke is a stroke (infarct) which does not have any outward symptoms (asymptomatic), and the patient is typically unaware they have suffered a stroke. Despite not causing identifiable symptoms a silent stroke still causes damage to the brain, and places the patient at increased risk for a major stroke in the future. Silent strokes typically cause lesions which are detected via the use of neuroimaging such as MRI.
  • the term “reperfusion injury” refers to tissue damage caused when blood supply returns to the tissue after a period of ischemia.
  • the absence of oxygen and nutrients from blood creates a condition in which the restoration of circulation results in inflammation and oxidative damage through the induction of oxidative stress rather than restoration of normal function.
  • the damage of reperfusion injury is due in part to the inflammatory response of damaged tissues.
  • White blood cells carried to the area by the newly returning blood, release a host of inflammatory factors such as interleukins as well as free radicals in response to tissue damage.
  • the restored blood flow reintroduces oxygen within cells that damages cellular proteins, DNA, and the plasma membrane. Damage to the cell's membrane may in turn cause the release of more free radicals.
  • Such reactive species may also act indirectly in redox signalling to turn on apoptosis.
  • Leukocytes may also build up in small capillaries, obstructing them and leading to more ischemia.
  • red blood cell (RBC) transits through the capillary bed show extreme spatiotemporal heterogeneity, with characteristic changes during physiological challenges such as neural activity, decreased perfusion pressure and hypoxia, and in diseases such as ischemia and critical illness.
  • CTH capillary transit time heterogeneity
  • contractile capillary pericyte the cell type found by Krogh and colleagues to adjust capillary flows, however, remains unknown.
  • hypotension refers to abnormally low blood pressure, i.e. a mean arterial blood pressure (MABP) below 80 mmHg for an adult human, and below 100 mmHg for an adult rat. Hypotension may be associated with shock.
  • MABP mean arterial blood pressure
  • Hemorrhagic hypotension refers to hypotension as a result from blood loss.
  • neurodegenerative refers to the progressive loss of structure or function of neurons, including death of neurons.
  • Neurodegenerative diseases including Parkinson's, Dementia, Alzheimer's, multiple sclerosis, and Huntington's occur as a result of neurodegenerative processes.
  • Parkinson's disease refers to a degenerative disorder (neurodegenerative disease) of the central nervous system that impairs motor skills, cognitive processes, and other functions.
  • the most obvious symptoms are motor-related, including tremor, rigidity, slowness of movement, and postural instability.
  • non-motor symptoms are autonomic dysfunction and sensory and sleep difficulties.
  • Cognitive and neurobehavioral problems, including dementia are common in the advanced stages of the disease. PD usually appears around the age of 60, although there are young-onset cases.
  • the term “early detection of Parkinson's disease” refers to detection before the onset of clinical symptoms (bradykinesia, tremor, postural instability and rigidity). At this stage 50-80 percent of the dopamine-producing neurons have degenerated. If it were possible to detect the disease earlier, neuron-protective strategies could be exploited to delay the onset of PD. Thus, “early detection of Parkinson's disease” is also to be understood as detection before 50%, such as before 60%, such as before 70%, or such as before 80% of the dopamine-producing neurons have degenerated.
  • Dementia is a non-specific illness syndrome (set of signs and symptoms) in which affected areas of cognition may be memory, attention, language, and problem solving. It is normally required to be present for at least 6 months to be diagnosed. Cognitive dysfunction that has been seen only over shorter times, in particular less than weeks, must be termed delirium. In all types of general cognitive dysfunction, higher mental functions are affected first in the process.
  • Various types of brain injury, occurring as a single event, may cause irreversible but fixed cognitive impairment. Traumatic brain injury may cause generalized damage to the white matter of the brain (diffuse axonal injury), or more localized damage (as also may neurosurgery). A temporary reduction in the brain's supply of blood or oxygen may lead to hypoxic-ischemic injury.
  • Strokes ischemic stroke, or intracerebral, subarachnoid, subdural or extradural hemorrhage) or infections (meningitis and/or encephalitis) affecting the brain
  • prolonged epileptic seizures and acute hydrocephalus may also have long-term effects on cognition.
  • Excessive alcohol use may cause alcohol dementia, Wernicke's encephalopathy and/or Korsakoff's psychosis, and certain other recreational drugs may cause substance-induced persisting dementia; once overuse ceases, the cognitive impairment is persistent but not progressive.
  • multiple sclerosis refers to an inflammatory disease in which the fatty myelin sheaths around the axons of the brain and spinal cord are damaged, leading to demyelination and scarring as well as a broad spectrum of signs and symptoms.
  • Neoplasm is an abnormal mass of tissue as a result of neoplasia. Neoplasia is the abnormal proliferation of cells. The growth of neoplastic cells exceeds and is not coordinated with that of the normal tissues around it. The growth persists in the same excessive manner even after cessation of the stimuli. It usually causes a lump or tumor. Neoplasms may be benign, pre-malignant (carcinoma in situ) or malignant (cancer). In the present context, the term “malignant tumor” refers to “malignant neoplasm”.
  • carcinoma refers to an invasive malignant tumor consisting of transformed epithelial cells.
  • a malignant tumor composed of transformed cells of unknown histogenesis, but which possess specific molecular or histological characteristics that are associated with epithelial cells, such as the production of cytokeratins or intercellular bridges.
  • sarcoma refers to a cancer that arises from transformed connective tissue cells. These cells originate from embryonic mesoderm, or middle layer, which forms the bone, cartilage, and fat tissues. For example, osteosarcoma arises from bone, chondrosarcoma arises from cartilage, and leiomyosarcoma arises from smooth muscle, and soft tissue sarcoma refers to tumors of soft tissue.
  • Malignant tumors of the male reproductive organs include, but are not limited to prostate and testicular cancer.
  • Malignant tumors of the female reproductive organs include, but are not limited to endometrial, cervical, ovarian, vaginal, and vulvar cancer, as well as sarcoma of the uterus.
  • Malignant tumors of the digestive tract include, but are not limited to anal, colon, colorectal, esophageal, gallbladder, gastric, pancreatic, rectal, small-intestine, and salivary gland cancers.
  • Malignant tumors of the urinary tract include, but are not limited to bladder, penile, kidney, renal pelvis, ureter, and urethral cancers.
  • Receiver operating characteristic (ROC) curve analysis is a classification model for a mapping of instances into a certain class/group. Receiver operating characteristic (ROC) curve analysis may be used determine the classifier boundary between groups of patients for which the classifier boundary between classes must be determined by a threshold value, for instance to determine whether a person is likely to have a disease (e.g. Parkinsons disease) or if a patient is likely to respond to a treatment or not.
  • a disease e.g. Parkinsons disease
  • the processor is further arranged for assessing one, or more, of the first indicator, the second indicator, and the extraction capacity with a database comprising reference values thereof.
  • system further comprises a database with references levels of one, or more, of the first indicator, the second indicator and the extraction capacity for one or more subjects with:
  • the different reference levels may further be divided in groups according to age, sex/gender, degree of condition, pre-clinical stage etc.
  • One aspect of the present invention relates to the use of the ultrasonic system for monitoring the possible effect of a substance (e.g. an active pharmaceutical ingredient (API)) or a composition (e.g. one or more active pharmaceutical ingredients and one or more excipients) on the micro-vascular flow distribution of a tissue portion of a mammal.
  • a substance e.g. an active pharmaceutical ingredient (API)
  • a composition e.g. one or more active pharmaceutical ingredients and one or more excipients
  • active pharmaceutical ingredient refers to any substance that is biologically active.
  • excipient refers to the substance of the tablet, or the liquid the API is suspended in.
  • Another aspect of the present invention relates to a database comprising references levels of one, or more, of the first indicator, the second indicator and the extraction capacity for one or more subjects with:
  • FIG. 10 is a schematic drawing with an ultrasonic system 100 an ultrasonic system for measuring a micro-vascular flow distribution of a tissue portion 20 of a mammal; the system comprising:
  • transducer could in the context also be included to mean a plurality of transducers forming an ultrasonic imaging/monitoring modality for various modes of ultrasonic imaging.
  • the obtained extraction capacity EC may be transferred to an assessment step or procedure (ASSESS), e.g. a medical professional may perform a diagnostic assessment based on a displayed value.
  • ASSESS an assessment step or procedure
  • a medical professional may perform a diagnostic assessment based on a displayed value.
  • the first and the second indicator are also applied in the assessment.
  • a corresponding database DB may guide or assist in the assessment.
  • the database may be adapted for performing a partially or fully automated medical assessment, subject to verification by a medical professional.
  • tissue portion 20 including the capillary bed 10 , does not form part of the system 100 .
  • FIG. 11 is another embodiment of an ultrasonic system 100 for measuring a micro-vascular flow distribution of a tissue portion when subjected to the drug or medicine indicated as “X”.
  • system further comprises:
  • biomarker refers to substances or measurable parameters related to pericyte, basement membrane or endothelial cell conditions, such as the flow (velocity and density) of the formed elements of the blood, the diameter of capillaries and blood vessels in general, the oxygen tension and/or pH in and around the capillary bed, NO (nitrogenmonoxide), and lactate.
  • system further comprises:
  • the information about the active pharmaceutical ingredient level may be provided to the system, e.g. entered manually into a database being part of the system.
  • the system further comprises a second processor capable of using the first and the second indicator to estimate an extraction capacity (EC) of a substance (e.g. O 2 ) in said capillary bed.
  • EC extraction capacity
  • the first and/or second processor is further arranged for comparing said extraction capacity (EC) and/or heterogeneity ( ⁇ ) as a function of said biomarker (NO, Lactate) level and said active pharmaceutical ingredient (X) level.
  • Functional magnetic resonance imaging (fMRI) and positron emission tomography use cerebral blood flow (CBF), blood volume (CBV) and blood deoxygenation changes as proxies for neuronal activity, and for vasodilatory adaptation to low cerebral perfusion pressure (CPP). Findings of increased oxygen extraction without parallel CBF or CBV changes during functional activation and in patients with cerebrovascular disease therefore challenge operational models of neurovascular coupling and autoregulation.
  • CBF cerebral blood flow
  • CBV blood volume
  • CCPP vasodilatory adaptation to low cerebral perfusion pressure
  • Functional recruitment may be as important as CBF to increase oxygen delivery during functional activation, and may provide a metabolic reserve in stages of reduced CPP.
  • Cerebral blood flow is regulated to meet the brain's metabolic needs during neuronal activity and changing cerebral perfusion pressure (CPP).
  • CPP cerebral perfusion pressure
  • positron emission tomography PET
  • CBV cerebral blood volume
  • CMRO 2 cerebral metabolic rate of oxygen consumption
  • Patient 1 a 63 year old male with episodic left-sided hemiparesis caused by occluded right ICA, and patient 2, a 58 year old male with episodes of right-sided blindness due to a 90% stenosis of the right internal carotid, were both examined by PET and PWI. They presented no neurological deficits at the time of examination. Subjects were first [ 15 O] PET scanned, followed by Perfusion Weighted Imaging. Blood pressure, pulse and blood oxygen saturation were monitored throughout both scanning sessions. Written informed consent was obtained from both subjects, and the study was approved by the Regional Committee on Research Ethics. PET scans were acquired and analyzed as described by Ashkanian et al.
  • CBF cerebral blood flow
  • CMRO 2 oxygen metabolism
  • the inventors analyzed the role of capillary flow distributions in terms of supporting tissue oxygenation.
  • the idea dates back to August Krogh, who in 1920 demonstrated the capillary motor regulating mechanism: Capillary pericytes may open capillaries, thereby redistributing flow (so-called recruitment), such that the extraction of oxygen is increased.
  • the phenomenon was later abandoned in brain (and all tissues except muscle), as closed capillaries are generally not observed—yet the role of rapid changes in capillary flow patterns observed in response to local cellular activity, remains unknown.
  • the inventors successfully solved the complex set of equations that govern the biophysics of oxygen transport in tissue, and can now explain the profound implications of this phenomenon in detail. In particular, they are able to show how oxygen delivery to tissue depends not only on tissue blood flow—which is perhaps the most commonly assumed paradigm in the study and management of disease—but also on capillary transit time patterns.
  • the model thereby adds important new insights into other unsolved problems within neuroscience. From the current controversies over the BOLD effect in MRI neuroimaging to the significance of capillary microangiopathy and pericyte loss observed in conditions such as ageing, hypertension, diabetes, Alzheimer's Disease and Parkinson's Disease. Bell and colleagues (Neuron, Nov. 4, 2010) recently reported that age-dependent vascular damage in pericyte-deficient mice precedes neuronal degenerative changes, learning and memory impairment, and the neuroinflammatory response. This study suggest that the parallel disturbance of capillary flows—and thereby the ability engage this capillary oxygen reserve' during any sort of functional or physiological challenge—may play an independent role in the pathogenesis of these conditions.
  • the model also shows a disturbing property of capillary oxygen delivery. Slight disturbances in the heterogeneity of capillary flows, which has been established in for example ischemia and critical illness, cause paradox physiological state of malignant capillary transit time heterogeneity, in which attempts to increase blood flow leads to global hypoxia as well as local hyper-oxygenation.
  • CTTH capillary transit time heterogeneity
  • the inventors propose the existence of a neurocapillary coupling and speculate that capillary pericytes affect tissue oxygenation during increased oxygen needs by this mechanism, irrespective of their effect on arteriolar tone.
  • FIG. 4 shows arteriolar, capillary and venular oxygenations in the case of ‘actual’ transit time distribution measured in the resting rat brain (FIG. 4 . a .) by Stefanovic and colleagues (Stefanovic et al., 2008), and in the case of homogenous capillary transit times (FIG. 4 . b .), which corresponds to our current notion of purely ‘arteriolar’ regulation of oxygen delivery, and for an.
  • FIG. 6 . a shows the combined contour and intensity plot of the oxygen extraction capacity (OEC—the maximal fraction of oxygen that can biophysically be extracted from blood), as a function of the mean transit time (MTT or sometimes abbreviated p) and transit time heterogeneity a.
  • OEC oxygen extraction capacity
  • MTT mean transit time
  • p transit time heterogeneity
  • C A the arterial concentration of oxygen.
  • ⁇ CBV/CBF (Stewart, 1894), where CBV in our case refers only to the fractional volume of blood vessels from which oxygen can diffuse across vessel walls.
  • FIG. 6 depicts the dependence of CMRO 2 t on transit time in two cases:
  • oxygen extraction is assumed to occur in capillaries only.
  • capillaries allow only passage of single files of RBCs, the capillary blood volume is fixed from the perspective of oxygen transporting blood.
  • FIG. 6 . c oxygen diffusion is allowed to occur in larger vessels such as arterioles (Pittman, 2011), which may dilate in parallel with flow and therefore cause a smaller increase in ⁇ for a given CBF increase.
  • arterioles Pier, 2011
  • We chose a very conservative, empirical CBF-CBV relation based on total blood volume changes observed by PET in brain, proposed by Grubb and colleagues (Grubb et al., 1974). Note that the most efficient oxygen extraction again occurs for a homogeneous transit time distribution ( ⁇ 0).
  • FIG. 6 . b A surprising phenomenon is noted in FIG. 6 . b .
  • CTTH intracranial pressure
  • FIG. 4 . c displays the relation assuming Grubbs relation, in which relatively large CBF increases only result in small mean transit time changes, due to the parallel vasodilation. Therefore, although CTTH reduction accounted for over 50% of the additional oxygen delivery, this assumption probably underestimates the importance of CTTH reduction on oxygen transport. Note that the combined effect of an CBF increase and CTTH reduction produce an almost linear increase in extracted oxygen with flow, unlike the more disproportionate increase in CBF needed to explain a given increase in oxygen utilization in previous models (Buxton and Frank, 1997; Fox and Raichle, 1986; Hyder et al., 1998; Vafaee and Gjedde, 2000). FIG. 4 . d .
  • FIG. 5 shows the relation between OEC and blood flow transit time for negligible and high tissue oxygen tensions.
  • the main effect of a finite tissue oxygen tension is to reduce the maximum attainable OEC, while increasing the slope of the CMRO 2 —CBF relation (Reducing the blood-tissue oxygen concentration gradient gradually eliminates the contribution of fast-flowing RBCs, who display poor extraction efficiency, to the slope of the curve).
  • This property hence enhances the oxygen release by a sudden increase in blood flow and/or CTTH reduction due to physiological stimuli such as those studied below, or vasomotion.
  • the table in FIG. 3 shows data from all available in vivo recordings, in which transit time characteristics were reported in such a manner that our model could be applied with limited assumptions. These were all performed in rat brain.
  • CTTH is large ( ⁇ relative to ⁇ ) in the control states of all studies, emphasizing the importance of incorporating CTTH in models of oxygen transport.
  • the ⁇ and ⁇ values determined in the various physiological states are illustrated in the OEC and CMRO 2 t contour plots in FIG. 6 .
  • CMRO 2 t were within 20% of those inferred from independent flow change estimates, and within measured values of oxygen metabolism and oxidative glucose utilization in ⁇ -chloralose anesthetized rats during forepaw stimulation by localized spectroscopy (Hyder et al., 1996). Note that biophysically, CTTH reductions accounted for more than 32% of the increased oxygen delivery during functional activation by the most conservative assumptions (negligible extracapillary oxygen tension, and Grubbs relation). If we assume non-negligible tissue oxygen tension, and (more realistically) constant volume of oxygen exchanging vessels, half if not all (FIG. 4 . d .) of the additional oxygenation for functional activation depended on CTTH reductions.
  • FIG. 3 shows the dynamics of transit time and CTTH changes during the reported physiological stimuli in the OEC and contour plots. Note that in ischemia (reduced CBF), the model predicts metabolic benefits of maintaining low flow heterogeneity and the lowest possible mean transit time (i.e. blood volume), given the available blood flow.
  • FIGS. 7 . e . and 7 . f . show values of OEC and MTT, averaged over the affected and unaffected hemispheres, for each image slice in both patients.
  • FIG. 3 and FIG. 6 show that (with the exception of severe hypotension); CTTH reductions counteracted the OEC-lowering effects of CBF increases across varying degrees of vasodilation.
  • CTTH Good's relation and negligible tissue oxygen tension
  • reduction of CTTH was necessary to maintain appropriate oxygenation, both for resting state metabolism during hypoxia, and to fuel cortical activity during somatosensory or cortical electrical activation.
  • the model developed here extends existing models of oxygen extraction in tissue by including the effects of CTTH, based on capillary transit time properties available from in vivo microscopy studies.
  • our model demonstrate that it is a basic property of the parallel organization of capillaries that oxygen extraction capacity depends not only on arterial and arteriolar tone as hitherto believed (as quantified by the mean transit time, the x-axis in FIG. 6 ), but also to a large extent on the distribution of capillary transit times (as quantified by the standard deviation of capillary transit times, the y-axis in FIG. 6 ).
  • the model thereby extends the original notion of capillary recruitment (Krogh, 1919) by showing that is represent merely an extreme case of capillary transit time heterogeneity, while changes in CTTH alone (with all capillaries open) may alter the effective capillary surface area available for diffusion several-fold (FIG. 6 . d .).
  • FIG. 7 provides first evidence that changes in CTTH may be involved in maintaining tissue oxygenation (by increasing OEF) in carotid stenosis.
  • Our model predicts that maintenance of low CBV (and hence low p for a given CBF) and low CTTH represent the most favorable hemodynamic state in a state of limited blood supply (reduced CPP).
  • CTTH malignant CTTH
  • CTTH reduction is an actively regulated mechanism, or a passive effect of the increased RBC flux in states of high CBF, remains poorly understood.
  • the studies analyzed here generally showed decreasing CTTH as a function of flow.
  • the notion of a passive process is contradicted by findings of reduced CTTH in hypocapnic rats (Vogel et al., 1996), where CBF is significantly reduced, and in some cases of acute human stroke ( ⁇ stergaard et al., 2000).
  • Capillary pericytes are contractile cells, found on the abluminal side of endothelial cells, and increasing in vitro evidence suggest that they contract and dilate in response to local blood pressure and cellular activity (Diaz-Flores et al., 2009).
  • pericyte action is key to the neurocapillary coupling mechanism described above, as generalized pericyte dilation permits more homogenous flow of RBC in response to local release of neurotransmitters (Peppiatt et al., 2006)—and hence higher OEC, irrespective of parallel flow increase.
  • pericyte constriction is believed to affect the passage of RBC only. Indeed, Vogel and colleagues, showed that the extent of CTTH depends on the presence of RBCs, supporting the role of pericytes in regulating CTTH (Vogel et al., 1997).
  • the application of the model is currently limited to data obtained by direct observations of RBC passage in superficial capillaries in animals. While technical advances may extend such microscopic techniques to deeper structures (Barretto et al., 2011) in rodent brain, we are currently extending neuroimaging based measurements of capillary blood retention in humans to assess CTTH noninvasively in humans ( ⁇ stergaard et al., 1999), as reported above. In terms of model limitations, we have assumed a constant value of the oxygen tension in tissue immediately outside the capillaries, in line with the recently suggested ‘revised oxygen limitation hypothesis’, according to which blood supply is regulated so as to maintain a constant, non-vanishing oxygen tension (Buxton, 2010).
  • tissue oxygen tension is likely to be heterogeneous, possibly fluctuating in time (Ndubuizu and LaManna, 2007).
  • Our assumption of a tissue oxygen tension that remains constant in space and time may therefore be a simplification.
  • our current model captures the qualitative implications of capillary flow heterogeneity, but future studies should analyze the influence of a biologically more realistic distribution of tissue oxygenation.
  • the effects of non-negligible oxygen tension suggest that oxygen tension gradients in tissue represent an additional dynamic parameter that affects the brain's ability to regulate oxygen supply over short time scales.
  • Capillary transit time distributions therefore reflect the underlying distribution of capillary lengths, as well as the velocity distribution of RBCs. Also, capillary branching, with interconnections to other capillaries, tends to equilibrate oxygen tensions across some parallel capillary paths. These aspects mostly affect the estimation of absolute transit time heterogeneities from literature data that report these in terms of blood flow, RBC velocities, or cell fluxes, and do not reduce the quantitative effects of CTTH changes reported here.
  • h ⁇ ( ⁇ ) 1 ⁇ ⁇ ⁇ ⁇ ⁇ ( ⁇ ) ⁇ ⁇ ⁇ - 1 ⁇ ⁇ - ⁇ / ⁇ , ( 1 )
  • CV coefficient of variation
  • CMRO 2 t To incorporate the effect of flow heterogeneity on the upper biophysical limit for the proportion of oxygen that may be extracted by tissue, oxygen extraction capacity (OEC), and hence the upper limit on the cerebral metabolic rate of oxygen that can supported, CMRO 2 t , we first model the dependence of oxygen extraction Q( ⁇ ) on transit time ⁇ , and then compute CMRO 2 max by integrating over the distribution h( ⁇ ) of transit times.
  • OEC oxygen extraction capacity
  • CMRO 2 CBF ⁇ C A ⁇ OEF, where C A is arterial oxygen concentration, and
  • C B is the concentration of bound oxygen
  • B is the maximum amount of oxygen bound to hemoglobin
  • P oxygen partial pressure in plasma
  • P 50 is the oxygen pressure required for half saturation
  • h is the Hill coefficient.
  • ⁇ H is Henry's constant.
  • Equation (7) enables us to average over the gamma distribution yielding:
  • OEC ⁇ ( ⁇ , ⁇ ) Q max ( 1 - 1 ⁇ ⁇ ( ⁇ ) ⁇ ⁇ n ⁇ ⁇ q n ⁇ ( k ⁇ ⁇ ⁇ ) n ⁇ ⁇ ⁇ ( n + ⁇ ) ( rk ⁇ ⁇ ⁇ + 1 ) n + ⁇ ) ( 8 )
  • OEC does not rely on independent measurements of absolute CBF, only the determination of transit time distribution, either by direct observation of RBC velocities by in vivo imaging techniques, or by residue detection experiments, tracking the passage of intravascular ultrasound, MR or CT contrast bolus passage ( ⁇ stergaard et al., 1999).
  • PS ⁇ CBF ln(1 ⁇ OEC ) (10).
  • the change in the apparent PS product depends on the type of tracer through the value of the rate constant k.
  • the explicit formula becomes
  • C aO2 19 mL/100 mL was assumed in the resting state.
  • MRI was performed on a 3.0 T Signa Excite HR GE Imager (General Electrics Medical Systems, Waukesha, Wis., U.S.A.).
  • perfusion imaging was performed by acquiring dynamic Gradient Recalled Echo Planar Imaging (EPI) (Time of Repetition 1500 ms, time of echo 30 ms) during the passage of a 0.1 mmol/kg bolus of gadobutrol (Gadovist®, Bayer Schering Diagnostics AG, Berlin) injected at a rate of 5 ml/s, followed by a 20 ml bolus of saline.
  • EPI Echo Planar Imaging
  • RBC red blood cell
  • the value of the rate constant k was found by using the mean transit time and heterogeneity of healthy patients and assuming an OEC of 0.3.
  • ‘h’ refer to healthy patients, ‘d’ to diabetic patients, and the numbers one through four to the categories of the diabetic patients above.
  • Alzheimer's Disease Increases Oxygen Extraction Capacity in Temporoparietal Lobe Due to Impaired Perfusion
  • Alzheimer's Disease is considered a neurodegenerative disease, characterized by abnormal beta-amyloid metabolism and the formation of amyloid plaques and neurofibrillary tangles in the brain parenchyma.
  • the inventors have developed a model that allow assessment of the upper, biophysical limit to oxygen delivery to tissue based on residue detection data from conventional computerized tomography (CT) or magnetic resonance imaging (MRI), allowing direct assessment of microvascular limitations to oxygen delivery in patients.
  • CT computerized tomography
  • MRI magnetic resonance imaging
  • Alzheimer's disease is associated with a loss of normal capillary flow heterogeneity, and that the resulting changes in oxygen extraction capacity correlates with patients' symptomatology.
  • GRE-EPI was performed during intra-venous bolus injection (5 ml/sec) of 0.2 mmol/kg gadobutrol (Gadovist®1.0 M, Schering) flushed by 20 ml saline.
  • the perfusion data was used to estimate CBV, CBF, MTT, OEC and FH.
  • the signal intensities were converted to concentration-time curves by:
  • C(t) ⁇ ln(S(t)/S 0 )*(1/TE), where C(t) is the concentration, S(t) is the signal intensity and S 0 is the baseline signal intensity.
  • the contrast agent diluted in the tissue is given by:
  • C a is the arterial input function.
  • CBF is blood flow in tissue.
  • R(t ⁇ ) is the residue function describing the fraction of tracer still present in the tissue at time t and by means of residue function the hemodynamic in the voxel can be derived.
  • the impulse to the system is arterial input function C a
  • the impulse response is the measured concentration C and let the residue function be expressed by
  • CBV is the area of R
  • CBF is the maximum of R
  • MTT is the product of ⁇ and ⁇
  • OEC is given by 1 ⁇ (1+P c ⁇ ) ⁇
  • P c is the oxygen exchange rate constant
  • FH is the standard deviation of the residue function.
  • the statistical analysis was performed in the frontal lobe, temporal lobe and parietal lobe. To minimize inter-subject variations in perfusion values, the individual co-registered perfusion maps were normalized in order to mean perfusion value in white matter in semioval center. Two-sample t-test was used for ROI analysis of the mean perfusion values in the frontal, temporal and parietal lobe.
  • FIG. 13 gives the summary of the ROI analysis. Mean OEC and FH are significantly higher in patients compared with controls. In the Temporal lobe we observed no significant differences in OEC or FH between patients and controls. More experiments using ultrasonic imaging are contemplated.
  • DSC-MRI Dynamic Susceptibility Contrast MRI
  • CBF cerebral blood flow
  • MTT mean transit time
  • Non-parametric methods such as standard singular value decomposition (sSVD) or the timing-insensitive, block-circulant variant (oSVD), are commonly used to estimate perfusion parameters, but these met
  • AUC receiver operating characteristics curve
  • FIG. 14 further indicates the similarity between oMTT and sMTT.
  • performance of pMTT was higher in 15 out of 16 patients (Exact binomial test, p ⁇ 0.001).
  • a 53-year old male was admitted after symptoms of stroke admitted after acute onset of left sided hemiparesis due to MCA thrombosis.
  • a bolus of 0.3 ml ultrasound contrast agent (SonoVue®, Bracco, Milano, Italy; solution prepared as recommended) followed by 5 ml saline flush was administered while obtaining a 2 min. cine-loop of the above described part of the brain.
  • the ultrasound system settings were the following: frame rate: 18 Hz, gain: 57%/63% (ipsi/contra) and compression: 50.
  • FIG. 17 shows contrast enhanced ultrasound (CEU) results from the unaffected hemisphere on an acute stroke patient.
  • FIG. 17 . a shows a Doppler image of contra-laterale parietal lobe with superimposed ROI.
  • FIG. 17 . b shows manually selected tissue curve (lower) and AIF (upper).
  • FIG. 17 . c shows gamma variate fit using the parametric vascular model. The dashed line indicates the fitted gamma variate and the solid line indicates the ground-truth tissue curve.
  • FIG. 18 shows contrast enhanced ultrasound (CEU) results from the affected hemisphere on an acute stroke patient.
  • FIG. 18 . a shows Doppler image of ipsi-laterale parietal lobe with superimposed ROI.
  • FIG. 18 . b shows manually selected tissue curve (lower) and AIF (upper).
  • FIG. 18 . c shows gamma variate fit using the parametric vascular model. The dashed line indicates the fitted gamma variate and the solid line indicates the ground-truth tissue curve.
  • OEC Oxygen Extraction Capacity
  • Imaging techniques such as Magnetic Resonance Imaging (MRI), Positron Emission Tomography (PET) and Computer Tomography (CT) are currently used to assess capillary blood flow.
  • CEU contrast-enhanced ultrasound
  • Ultrasound contrast agents may contain micro-bubbles, mostly consisting of low solubility gas in a lipid shell. They are entirely confined to the intravascular space as opposed to CT and MRI contrast agents and are therefore superior in visualizing and quantifying microvasculature.
  • ultrasound images are captured at a very high frame (max 42 Hz) and in high resolution (600 ⁇ 800). Therefore steps to reduce the excessive data amount are needed to keep the processing time as low as possible.
  • Images obtained by ultrasound are logarithmic compressed in order to facilitate visual interpretation. Therefore, we lineralize the data in order to obtain linear relationship between the contrast concentration and image intensity. Subsequently, a temporal low-pass filtration and down sampling of data is performed achieving a repetition time (TR) of 0.83 s. Finally, the images are spatially averaged and down-sampled by a factor 0.25. The images are averaged in regions to improve the SNR and are afterwards down-sampled to remove redundant data. Cf. FIG. 19 for a corresponding flow-chart.
  • OEC In order to determine voxel-wise OEC we use the parametric vascular model [1] to estimate the ⁇ and ⁇ parameters of the residue function. OEC is given as:
  • FIG. 20 showing the temporal approach visualizing parts of the ipsilateral temporal and parietal lobe along with the ipsilateral M2 segment of the middle cerebral artery and the C6 and C7 segment of the internal carotid artery.
  • a venous cannula is inserted into an antecubital vein.
  • a bolus of 0.3 ml ultrasound contrast agent (SonoVue®, Bracco, Milano, Italy; solution prepared as recommended by the producer) followed by 5 ml saline flush are administered while obtaining a 2 min. cine-loop of the above described part of the brain.
  • the ultrasound system settings are the following: frame rate: 7 Hz, gain: 81% and compression: 38. Acquired image sequences are saved in DICOM format and subsequently transferred to an off-line workstation.
  • the same ultrasound system as in the brain model is applied (Philips iU22 xMATRIX) using a L9-3 linear array transducer.
  • the ultrasound system settings are the following: Frame rate: 42 Hz, gain: 40% and compression: 58.
  • An adult male mouse with an implanted tumor (mammary adenocarcinoma) on the lower back is transferred to a holding device.
  • a vessel is formed with modelling clay around the animal lower part cf. FIG. 21 .
  • the lateral tail vein is used to inject diluted ultrasound contrast agent.
  • a total amount of 160 nl Sonovue® in a 200 ⁇ l bolus is injected.
  • a 2 min. image sequence in the region of the tumor is recorded while contrast is passing through the microvasculature. Image data are then transferred to an off-line workstation for post-processing.
  • FIG. 21 shows an experimental set-up with a carefully restrained mouse using modelling clay to stabilize the ultrasound jelly around the tumor.
  • FIG. 22 show on the left: Oblique scan plane through the temporal acoustic window showing the region of the arterial input function (AIF) in lower circle and the assessed tissue area in marked up color.
  • FIG. 22 shows on the right: The integrated signal intensities for both regions are plotted against time, the upper curve is AIF, and the lower curve is the concentration curve.
  • the arterial input (AIF) function is collected in the left common iliac artery.
  • the curve is dominated by a slow down-slope representing the high contrast agent concentration in the small total blood volume.
  • Two tissue curves are obtained: one in the partially necrotic center, one in the well-vascularized periphery.
  • the peripheral curve is characterized by a high and sharp up-slope and a slow down-slope, similar to the arterial input function.
  • the flat curve obtained from the center indicates insufficient blood supply ( FIG. 23 ).
  • ROI corresponding to FIG. 23 B the OEC was estimated to 0.14 and in ROI corresponding to FIG. 24 C the average OEC was estimated to 0.17.
  • FIG. 23 shows A) Transverse scan through the tumor and the mouse's lower abdomen with the region of the AIF and the tissue regions in two circles above.
  • (B) AIF curve and tissue curve from the periphery of the tumor in red.
  • (C) AIF upper curve and tissue curve from the partially necrotic center shown in the lower curve.
  • FIG. 24 shows OEC plots are calculated for the central and peripheral part of the tumor. As expected is the oxygen extraction increased in the ischemic part compared to the well-vascularized peripheral part.
  • OEC muscular OEC might reflect the degree of leg ischemia in patients with stenotic or occlusive peripheral vascular disease, and OEC measurements in suspected rejection of transplanted organs could possibly contribute with important diagnostic information.
  • OEC assessments are likely to have a considerable impact on treatment management in critically ill patients and should therefore be further developed.
  • CTTH capillary transit time heterogeneity
  • CTTH may also be a critical hemodynamic parameter in understanding different vascular diseases, such as type 2 diabetes (T2D).
  • Krogh argued that capillaries themselves are part of the regulation of nutrient supply by capillary recruitment (Krogh, 1919): i.e. opening of previously closed capillaries in order to augment the muscle's total capillary surface area available for substance diffusion.
  • Bohr-Kety-Crone-Renkin BKCR
  • BKCR Bohr-Kety-Crone-Renkin
  • both Krogh's CRM and the BKCR equation seem two perfect theories to demonstrate the adaptation of microvasculature in response to exercise: accordingly, at rest there is a great unused reserve in the capillary bed, which in response to exercise will open to meet the metabolic demands (i.e. capillary recruitment), consequently increasing the muscle's total capillary surface area for greater extraction of oxygen, glucose and free fatty acids as well as reducing the diffusion distance between capillary to mitochondrion (i.e. the BKCR equation).
  • capillary recruitment the metabolic demands
  • the BKCR equation the diffusion distance between capillary to mitochondrion
  • pericytes allow RBCs to transit through the entire capillary bed in a heterogeneous or gradually less heterogeneous fashion in order to supply oxygen according to the metabolic demand at rest or during exercise, respectively.
  • the BKCR equation may even help us more to appreciate capillary perfusion as dynamic and constantly changing.
  • the classical BKCR flow-diffusion equation is limited by its intrinsic extraction property based on only one idealised capillary, redefining the model gives us a far more accurate answer to the hemodynamics of capillary perfusion, including de facto that capillaries in muscle tissue are part of a highly interconnected and tortuous arrangement, which display great variability among muscle groups (reference).
  • the BKCR equation also predicts that any differences in perfusion among coupled capillaries reduce the efficacy of oxygen extraction relative to the model's estimates, however with an unaltered total capillary flow output.
  • Microcirculation already uses this property to maintain high oxygen extraction during high flow conditions: capillary transit time heterogeneity (CTTH) is reduced in response to increased metabolic demands (Kalliokoski et al., 2004). Therefore, the parallel coupling of capillaries in tissue compensates for the inherent, poor extraction efficacy of single capillaries at high flows (see FIG. 25 ) and, contrary to earlier beliefs, allows the capillary bed to regulate extraction efficacy, without traditional recruitment.
  • CTTH reduces concurrently with increasing blood flow during exercise in humans and different animals.
  • perfusion heterogeneity and CTTH are high, however greatly influenced by the character of the disease (Ellis et al., 2002; Humer et al., 1996; Kayar et al., 1994).
  • Study population A total of 10 test subjects (27.2 ⁇ 5.3 yr, 173 ⁇ 10 cm, 67.9 ⁇ 14.9 kg) volunteered for the experiment. Test subjects were recruited through advertisement at Department of Sports Science at Aarhus University. They were all given both oral and written information about the purpose, nature and potential risks before they gave a written informed consent to participate in the study. The subjects were requested to meet fasting and at least 3 hours after the subjects had eaten. Not any of the subjects were taking regular medication. The local Human subject Ethics Committee of Region Midtjylland approved the experiment and procedures applied.
  • Subjects with recent acute coronary syndrome or clinically unstable ischemic cardiac disorder e.g. myocardial infarction, acute heart failure or severe rhythm disorders
  • ischemic cardiac disorder e.g. myocardial infarction, acute heart failure or severe rhythm disorders
  • smoking, obesity, pregnancy and breast-feeding also excluded potential subjects.
  • Handgrip exercise decreased CTTH (see FIG. 26 ) by 56% from rest to 80% at their pre-determined maximal force (from 3.91 ⁇ 0.87 sec. at rest to 1.73 ⁇ 0.25 sec. at 80%, P ⁇ 0.02), and by 50% from 25% to 80% handgrip forces (from 3.42 ⁇ 0.56 sec. at 25% to 1.73 ⁇ 0.25 sec. at 80%, P ⁇ 0.01).
  • OEC increased in response to graded handgrip force (see FIG. 27 ). Consequently, OEC increased by 94% from rest to 80% handgrip force (30 ⁇ 3% at rest to 59 ⁇ 3% at 80%, P ⁇ 0.001). Furthermore, between 25% and 80% handgrip forces, OEC increased by 44% (41 ⁇ 4% at 25% handgrip force to 59 ⁇ 3% at 80% handgrip force, P ⁇ 0.01).
  • CTTH is a critical physiological parameter, because it may be one of the regulating factors to oxygen delivery to working skeletal muscles. Consequently, as oxygen diffuses across the capillary wall to muscle tissue, the time that blood stays in capillaries has a direct impact on the oxygen extraction (Honig & Odoroff, 1981).
  • changes in CTTH measured by the standard deviation a of transit time across the capillary bed
  • MBV/MP ratio expressed as mean ⁇
  • Kallikoski and co-workers demonstrated an oxygen extraction of 45 ⁇ 11% during isometric leg muscle contractions at 10% of maximal voluntary contraction (Kalliokoski et al., 2004).
  • Same research group conducted a similar study three years earlier, in which it demonstrated that trained subjects had an oxygen extraction of 49 ⁇ 14% versus untrained subjects, whose oxygen extraction capacities were 29 ⁇ 12% (Kalliokoski et al., 2001).
  • a mixed protocol of continuous and intermittent exercises revealed that the oxygen extractions during 10% isometric leg muscle contraction and 5% continuous static exercises were 37 ⁇ 22% and 30 ⁇ 23%, respectively (Kalliokoski et al., 2003b).
  • CTTH CTTH
  • PET- and MRI-scans have been considered the most accurate methods to measure regional muscle blood perfusion in humans (Frank et al., 1999). Additionally, NIRS has also proven highly accurate for same purposes (Boushel et al., 2000).
  • CEUS has gradually become an accepted method in muscle perfusion measurements during exercise (Womack et al., 2009; Krix et al., 2009; Rattigan et al., 2005).
  • Capillary transit time heterogeneity is an interesting—and perhaps a rather important—feature of the microcirculation, thus potentially being a prerequisite for changing oxygen extraction capacity.
  • CTTH and OEC approximately follow a hyperbola structure ( FIG. 28 ). Consequently, with these findings, we suggest that a gradual greater reduction of CTTH induces a gradual greater increase in OEC.
  • Kalliokoski and co-workers demonstrate that micro vascular transit time heterogeneity and oxygen extraction are weakly linearly correlated, though not graphically shown (Kalliokoski et al., 2004). However, together with our findings these results suggest that oxygen extraction capacity becomes gradually more dependent on the down regulation of capillary transit time heterogeneity as exercise becomes more strenuous (even without capillary recruitment).
  • CTTH may be a critical phenomenon, which increases muscle tissue oxygenation during graded muscle work and reduces oxygenation in the ischemic state.
  • pericytes contribute to the regulation of micro vascular circulation (D ⁇ az-Flores et al., 1991), these cells may also have a putative pharmacological function as well.
  • cardiovascular diseases whether it is e.g. acute myocardial infarction, heart failure or atherosclerosis (as seen in many patients with T2DM), all diseases show signs of varied dysoxygenation.
  • the existing therapies e.g. statins, antithrombotic and anti adrenergic drugs
  • these patients receive aim to normalise blood flow (reperfusion) or tissue oxygen utilisation (sources), consequently overlooking the potential function of capillaries to control local as well as global tissue oxygenation.
  • dysoxygenated blood vessels during different vascular diseases could be of highly relevant research, especially for future clinical therapy. This becomes even more interesting/relevant, as cardiovascular diseases account for huge, potentially increasing, economic burdens in total health care.
  • upcoming/future research should focus on whether dysoxygenation could originate in the blood cells, since current therapy seeking to reduce dysoxygenation has not fully been succeeded.
  • capillaries are such an integral part of muscle tissue oxygenation and in various diseases, such as type 2 diabetes. Furthermore, provided that this model is gradually extended, we will improve our understanding of the relationships between muscle tissue perfusion and power, contraction strength and oxygen uptake, which can be directly applied for pharmacological purposes in various oxygen-dependent diseases, such as hypoxia and ischemia.
  • AD Alzheimer's Disease
  • BOLD blood oxygen level dependent
  • CBF cerebral blood flow
  • Girouard and Iadecola 2006
  • disturbances in the integrity of the capillary bed The latter involve microvascular atrophy, physical disruptions of the capillary wall, and endothelial derived inflammatory and neurotoxic factors (Farkas and Luiten, 2001, Zlokovic, 2011). Changes of this type can be expected to result in hypoperfusion and a reduced supply of oxygen to brain tissue.
  • capillary disturbances have been observed as antecedents of neurodegenerative changes associated with dementia (Bell et al., 2010).
  • BKCR Bohr-Kety-Crone-Renkin
  • Capillary flow patterns are complex functions of capillary bed topology, blood viscosity, the adhesion of blood cells to capillary walls, factors that affect the local diameter of individual capillaries ( ⁇ 6-8 ⁇ m), and the relative number, deformability, and size of the blood cells ( ⁇ 8-15 ⁇ m).
  • FIG. 31 illustrates how the heterogeneity of capillary flows reduces the extraction of oxygen relative to that which would have been predicted from the BKCR paradigm ( ⁇ stergaard et al., 2000). In view of this observation, we have recently extended the BKCR model to include the effects of capillary transit time heterogeneity (Jespersen and ⁇ stergaard, 2012).
  • CTTH capillary transit time heterogeneity
  • CTTH also influences the maximum achievable oxygen extraction fraction (OEFmax) for a given tissue oxygen tension.
  • OEFmax maximum achievable oxygen extraction fraction
  • FIG. 3 . a . where the x-axis corresponds to the mean transit time (MTT) for blood as it passes through the capillary bed.
  • MTT mean transit time
  • Capillary MTT is defined as the ratio of the capillary CBV to the CBF (Stewart, 1894), that is, by the two central parameters in the original BKCR equation.
  • the y-axis corresponds to the CTTH, here expressed as the standard deviation of the transit times for the individual capillaries.
  • FIG. 31 . a . for any MTT an increase in CTTH results in a reduced OEFmax.
  • CMRO2 max the maximum oxygen consumption that can be supported, does not necessarily increase with CBF, as predicted by the original BKCR equation.
  • an increase in CBF, during which CTTH remains constant may paradoxically lead to a hemodynamic state with reduced oxygenation availability. States such as these have been referred to as malignant CTTH (Jespersen and ⁇ stergaard, 2012).
  • malignant CTTH Jespersen and ⁇ stergaard, 2012
  • FIG. 32 . b they correspond to combinations of CTTH and MTT that lie above the yellow line in FIG. 32 . b .
  • the extended BKCR equation predicts that the lowering of oxygen tension in the tissue becomes the means by which oxygen availability can be maintained.
  • CMRO2 max is plotted as a function of tissue oxygen tension (Pt) and CTTH.
  • Pt tissue oxygen tension
  • CTTH tissue oxygen tension
  • the extended BKCR equation predicts that any metabolic benefits of angiogenesis will depend on concomitant changes in CTTH and CBF values. Below the malignant CTTH levels (FIG. 32 . b .), increased capillary blood volume must be accompanied by an even greater increase in CBF in order to reduce MTT. Contrary to the predictions of the BKCR equation, angiogenesis will not result in an increase in oxygen availability, unless there is a parallel increase in CBF via normal vasomotor function. Instead, the extended BKCR equation predicts that compensatory angiogenesis in response to tissue hypoxia would tend to reduce the availability of oxygen in tissue when the hypoxia is accompanied by an impaired vasodilatory response, such as observed in AD (Girouard and Iadecola, 2006).
  • capillary dysfunction as an irreversible increase in CTTH, that is, the hemodynamic correlate of changes in capillaries or in blood that disturb the normal passage of erythrocytes through the capillary bed.
  • Sources of capillary dysfunction and reversible increases in CTTH are discussed further below.
  • the hypothesis presented here on the basis of the extended BKCR model, assumes that changes in CBF and tissue oxygen tension reflect attempts by the tissue to maintain tissue oxygenation.
  • the degree of capillary dysfunction, the CTTH value increases with time towards the right.
  • the graphs below this display the changes in CBF and tissue oxygen tension which are necessary to maintain tissue oxygenation over time, according to the extended BKCR model. To facilitate the comparison of these curves to the BOLD and CBF changes shown in FIG. 30 , the temporal dynamics of OEFmax are shown in the lower graph.
  • microvascular dysfunction is minimal (CTTH panel) and increases in resting and activity-related CBF levels can still compensate for any decrease in OEFmax.
  • This phase corresponds to the period during which young asymptomatic APOE ⁇ 4 carries have increased CBF values during rest (Fleisher et al., 2009a, Scarmeas et al., 2003) and relatively more pronounced CBF increases during functional activation (Scarmeas et al., 2005).
  • both the enhanced increase in CBF and the reduction in OEF, during functional activation are predicted to result in an increase in BOLD signals during this phase (Davis et al., 1998) (Davis.
  • These changes in BOLD signals are consistent with the observations made in young asymptomatic APOE-4 carries during memory retrieval tasks (Bondi et al., 2005, Bookheimer et al., 2000, Ringman et al., 2011).
  • the CTTH continues to increase, and the extended BKCR model predicts that net oxygen extraction becomes progressively more dependent on the oxygen concentration gradients that result from tissue hypoxia, rather than from increases in CBF.
  • the model further predicts that CBF responses will have to be suppressed if an optimal OEFmax is to be maintained.
  • suppression of the CBF responses which is a hallmark of neurovascular dysfunction, is observed in humans and in animal models of hypertension and AD (Jeuard and Iadecola, 2006).
  • ROS reactive oxygen species
  • HIF-1 hypoxia-inducible transcription factors
  • NOX-2 NADPH oxidase 2
  • NOX-2 is involved in electron transport across membranes and in the production of ROS as part of normal brain function (Kishida et al., 20(Sorce and Krause, 2009)05). However, high levels of NOX-2 in microglia, astrocytes, neurons, and cerebral vessels are also involved in oxidative cell damage during ageing and in a number of neurological disorders, including AD (Sorce and Krause, 2009). Oxidative cell damage is believed to be an early feature of the AD, in that oxidation of RNA and proteins precedes the deposition of A ⁇ (Nunomura et al., 2001).
  • ROS hypoxia-induced up-regulation of NOX-2 and the subsequent production of ROS can induce changes in arterioles that can benefit tissue oxygenation when CTTH is elevated.
  • ROS attenuates normal vasodilation and, according to the extended BKCR model, helps to maximize oxygen extraction.
  • Increased ROS-production also interferes with the regulation of CBF, in that the walls of small arteries and arterioles become thicker and more rigid as a result of prolonged oxidative damage.
  • vascular smooth muscle cells degenerate and develop abnormal focal constrictions that result in the narrowing of the vessel lumen.
  • Such permanent reductions in arteriolar diameter would replace the endogenous production of ROS as a means of reducing the CBF responses.
  • HIF-1 stimulates the expression of both human and animal ⁇ -amyloid precursor protein (APP) cleavage enzyme (BACE1), which leads to an increased production of A ⁇ (Zhang and Le, 2010).
  • BACE1 ⁇ -amyloid precursor protein
  • NFT neurofibrillary tangles
  • hypoxia impairs the degradation of A ⁇ , as well as the clearance of A ⁇ across the blood-brain barrier (BBB), and leads to increased levels of A ⁇ in the parenchyma (Zhang and Le, 2010, Zlokovic, 2010).
  • BBB blood-brain barrier
  • the role of hypoxia in AD is supported by the observation that APP23 transgenic mice subjected to hypoxia have increased A ⁇ 1-40 and A ⁇ 1-42 levels, increased plaque number, and exacerbated memory deficits (Sun et al., 2006).
  • High A ⁇ levels in turn, has been associated with neuronal dysfunction, neuroinflammation and neuronal loss (Hardy and Selkoe, 2002).
  • hypoxia-induced up-regulation of angiogenic factors in AD (Grammas et al., 2011).
  • capillary atrophy rather than angiogenesis
  • angiogenesis is a dominant feature of AD and AD models (Farkas and Luiten, 2001).
  • the extended BKCR model predicts that, in order for increased capillary volume to be metabolically beneficial, the CBF must also increase in parallel. This is unlikely to occur, however, because, as pointed out above, the blockage of upstream vasodilation invariably results in reductions in the CBF as the disease progresses.
  • the lack of angiogenesis, —and even the capillary rarefaction—observed in AD could therefore in fact be energetically favorable in view of parallel reductions in CBF.
  • the model presented here infers AD etiopathogenesis from the changes in tissue hemodynamics and tissue oxygen tension which must occur in order to maintain oxygen availability as risk-factor related CTTH increases accumulate over time.
  • the extended BKCR model predicts that increased CTTH causes profound dissociations of CBF and oxygen availability (Jespersen and ⁇ stergaard, 2012), and that compensatory changes in CBF and tissue oxygen tension to preserve tissue oxygen metabolism would result in neuroimaging findings in qualitative agreement with those found in asymptomatic high risk subjects prior to the diseases, and in MCI/AD.
  • the model predicts that neurovascular dysfunction and tissue hypoxia are necessary, but also sufficient means of maintaining tissue oxygenation for normal brain function. Consequently, the oxidative stress, the activation of inflammatory pathways and the amyloid formation commonly observed in AD could partly be viewed as long-term collateral damage, resulting from intrinsic attempts to secure short-term tissue oxygenation in response to capillary dysfunction.
  • the model applies more broadly to dementia conditions where microvascular changes occur, such as vascular dementia, and possibly the dementias observed in HIV and HCV, where capillary endothelium is specifically affected by viral infections.
  • the model may provide a framework for understanding the overlapping pathological features found in late-onset dementia (Fotuhi et al., 2009). It should be noted, that the duration of the proposed phases I-III may vary according to the local susceptibility of capillaries to specific vascular risk factors and local metabolic activity, giving rise to differences in regional neuronal degeneration, and symptom presentation.
  • Capillary morphology and in particular capillary wall structure, are profoundly altered in AD compared to normal ageing (Farkas and Luiten, 2001, Perlmutter and Chui, 1990). Capillaries appear atrophic, fragmented and irregular, with varying diameters. The inner wall, normally formed by specialized endothelial cells with tight junctions, often appear atrophic or swollen, with altered surface properties (Farkas and Luiten, 2001).
  • Endothelial cells are surrounded by capillary pericytes, which are key to the regulation of capillary diameter during functional activation (Fernandez-Klett et al., 2010), to blood brain barrier function (Armulik et al., 2010, Daneman et al., 2010), to angiogenesis (Dore-Duffy and LaManna, 2007), and to the brain's immune system (Thomas, 1999).
  • the fate of pericytes of in AD remain unclear as they have been reported to either undergo atrophy or to appear in a higher proportion in some capillary sections (Farkas and Luiten, 2001).
  • FIG. 32 summarizes the morphological changes in capillary wall structure and lumen in humans specimens, and in animal models (Farkas and Luiten, 2001)
  • pericytes The properties of pericytes in environments of elevated amyloid-levels have received special attention. Cultured human pericytes undergo degeneration when exposed to certain subtypes of A ⁇ (Verbeek et al., 1997). In both spontaneous and hereditary AD, pericytes express A ⁇ receptors which have been shown to be involved in the internalization of amyloid and subsequent pericyte death (Wilhelmus et al., 2007). Pericytes are believed to come in close contact with amyloid during the normal clearance of soluble amyloid through the perivascular space (Ball et al., 2010, Carare et al., 2008, Weller et al., 2008).
  • Amyloid-induced pericyte damage could change capillary morphology and function, and thereby, according to the model above, cause neurovascular dysfunction.
  • a ⁇ amyloid, and in particular the amyloid A ⁇ 1-40 subtype has been shown to attenuate normal vasodilator responses, owing to concomitant increase in the production of endothelial superoxide and a reduction in the bioavailability of NO (Iadecola et al., 1999, Niwa et al., 2001, Thomas et al., 1996).
  • ROS were recently shown to be derived from NADPH oxidases (Park et al., 2011).
  • Cardiovascular Disease have long been known to share the same risk factors (Breteler, 2000). Thickening of the capillary basement membrane is indeed a common feature of cardiovascular risk factors Studies in spontaneously hypertensive, stroke-prone rats show degeneration. The table below show findings in common AD risk factors.
  • angiotensin-II which is involved in the pathogenesis of hypertension, constricts a large proportion of freshly isolated retinal microvessels via activation of pericytic AT1 receptors (Kawamura et al., 2004). Meanwhile, in vivo administration of angiotensin-II attenuates upstream vasodilation during functional hyperemia and result in the release through NADPH oxidase derived radicals (Kazama et al., 2003, Kazama et al., 2004).
  • NFT neurofibrially tangles
  • CDR Clinical Dementia Rating
  • Pericytes are thus known to constrict in response to ROS production (Yemisci et al., 2009) and to NO depletion (Haefliger et al., 1994, Haefliger and Anderson, 1997).
  • ROS production Yemisci et al., 2009
  • NO depletion Haefliger et al., 1994, Haefliger and Anderson, 1997.
  • endogenous suppression of CBF could therefore lead to downstream reductions in OEFmax.
  • reductions in CTTH could, however, be irreversible, as we will discuss further below.
  • the proposed disease mechanism predicts that progression of the disease in closely linked to CTTH and CBF, and in particular, their combined proximity to the state of malignant CTTH, where hypoxia ensues, and CBF is argued to be suppressed by intrinsic production of ROS. Consequently, it would be expected that factors that increase CTTH, or factors which alter CBF would also affect disease severity. In particular, factors which temporarily increase CBF are expected to aggravate neurological symptoms and accelerate disease progression throughout Phase II. Meanwhile, and in contrast to theories proposing hypoperfusion as the primary cause of the disease, hypoperfusion would be expected to reduce oxidative stress and slow the progression of the disease throughout Phase II.
  • AD brain endothelial cells express elevated levels of inflammatory adhesion molecules, such as monocyte chemoattractant 1 (MCP-1), intercellular adhesion molecule-1 (ICAM-1) and cationic antimicrobial protein 37 (CAP37).
  • MCP-1 monocyte chemoattractant 1
  • IAM-1 intercellular adhesion molecule-1
  • CAP37 cationic antimicrobial protein 37
  • agents that relax capillary but not arteriolar tone may improve tissue oxygenation without eliciting deleterious hyperemia.
  • Blockage of ⁇ 2-adrenergic receptors (Zschauer et al., 1996), the AT-1 angiotensin II receptor system (Kawamura et al., 2004, Matsugi et al., 1997), and calcium channels are theoretically capable of inhibiting pericyte constriction and can be expected to improve tissue oxygenation by facilitating more homogenous capillary transit times.
  • Treatment of APP mice with an AT-1 blocker reduced the level of ROS in capillaries to levels similar to those recorded in wild-type mice.
  • NO is produced from L-arginine by NO synthases (NOS's) (Knowles et al., 1989). In mammalian tissues NO can also be produced from nitrite (Zweier et al., 1995). The nitrite in humans stems from either NO or dietary nitrate/nitrite (Bryan et al., 2005; van Faassen et al., 2009). Dietary nitrite consequently provides an accessible route for manipulation of the physiological levels of NO and would circumvent the need for pharmacological agents with the same effects.
  • Nitrite accomplishes this through the production of NO, which directly inhibits the mitochondrial complex I (Shiva et al., 2007). Nitrite also decreases NADPH oxidase activity and superoxide production (Montenegro et al.). Moreover dietary nitrate increases the production of mitochondrial ATP, by specifically reducing the uncoupling of protons across the mitochondrial membrane. This reduction allows the mitochondria to reduce the amount of oxygen needed to produce more ATP (Larsen et al., 2011).
  • Nitrite could act to decrease CTTH in response to neuronal activity, in that neuronal activity decreases local pH through the secretion of acid by astrocytes (Chesler, 2003). This would also allow nitrite to play a role at the capillary level in that astrocytic endfeet directly contact capillaries. ii) By reducing oxidative stress and the production of ROS's during hypoxic events, e.g. during neuronal activity in Phase II and III, nitrite could help reduce the amount of vascular and cellular injury in AD.
  • Nitrite could act to reduce the development of a malignant and irreversible increases in CTTH, by reducing the flow-reducing effects of vascular injury.
  • nitrite may ameliorate the progression of AD is that the intrathecal levels of nitrate in AD patients are inversely correlated with the degree of intellectual impairment (Tarkowski et al., 2000). It is also noteworthy that green leafy vegetables is the major dietary source of nitrate and a key part of the Mediterranean diet, which is reported to offer some protection against AD (Scarmeas et al., 2007). In addition, the therapeutic value of green leafy vegetables in hypertensive disorders appears to be related to their nitrate/nitrite content (Gilchrist et al., 2010).
  • PET using the glucose analog fluoro-deoxy-glucose (FDG) is widely used in routine diagnostic neuroimaging of patients suspected of having AD (Jagust, 2000). It is generally assumed that tracer uptake is proportional to glucose uptake even though FDG is not metabolized as glucose is. This has critical implications for the interpretation of FDG uptake data, in that both FDG and glucose blood-tissue clearance is limited by CTTH in much the same way as oxygen. Because FDG is not metabolized, it is not possible to compensate as it is for oxygen and glucose, by a higher blood-tissue concentration gradient.
  • FDG glucose analog fluoro-deoxy-glucose
  • PET combined with radiotracers with high affinity for amyloid and tau can, according to the model proposed here, provide high specificity and sensitivity to AD pathology that develops in both the hypoxic and subsequent degenerative phases (Small et al., 2006).
  • CTTH can, in theory, be determined from MR, CT, and ultrasound images acquired during the passage of erythrocytes through capillaries in the presence of an intravascular contrast agent (Ostergaard et al., 1999). These techniques have been used to demonstrate disturbed CTTH during acute ischemia ( ⁇ stergaard et al., 2000). In our own laboratory this approach has recently been used to quantify ⁇ , ⁇ and OEFmax (Mouridsen et al., 2011).
  • FIG. 34 shows an example of the application of this technique to a patient with AD, and to a somewhat older control-subject. Magnetic resonance imaging also permits measurement of CBF and BOLD-changes during the performance of standardized memory task. Of note is the measurement of the so-called resting state network activity, which does not depend on subjects ability to cooperate. This can be expected to be a particularly fruitful avenue for further exploration of the evolution of neurovascular dysfunction (Fleisher et al., 2009b)
  • capillary morphology, pericyte tone and RBC flow dynamics can be assessed in vivo with two-photon confocal microscopy (Fernandez-Klett et al., 2010, Stefanovic et al., 2008). Recording ⁇ and ⁇ across ensembles of capillaries can be used to calculate OEFmax and CMRO2 max ( FIG. 31 ). Similarly, Laser-Doppler recordings of the mean and standard deviation of RBC velocities permit of ⁇ and ⁇ to conveniently assessed (Jespersen and ⁇ stergaard, 2012).
  • a 40 kg pig was used to assess the functional hemodynamic of a kidney.
  • the kidney was evaluated in healthy state (Pre-intervention).
  • the main supplying artery (the renal artery) was clamped in 10 minutes and subsequently the kidney was evaluated by CEU (Post-occlusion).
  • CEU Post-occlusion
  • the pig underwent a systemic administered of streptococcal bacterium and was evaluated after 45 minutes (Septic shock) by CEU.
  • the ultrasound system settings were the following: framerate: 17 Hz, gain: 100% and compression: 50.
  • the raw data from the scanner was lineralized using an unscrambler-software developed by Phillips Healthcare.
  • a temporal low-pass filtration was performed achieving a repetition time (TR) of 1 s.
  • TR repetition time
  • the AIF was manually identified and the perfusion parameters were determined in a region-of-interest (ROI).
  • the perfusion parameters OEFmax, FH and MTT were determined using parametric vascular model.

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Cited By (10)

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WO2018176005A1 (fr) * 2017-03-24 2018-09-27 BURL Concepts, Inc. Dispositif à ultrasons portatif
WO2018213839A3 (fr) * 2017-05-19 2018-12-27 Mayo Foundation For Medical Education And Research Système et procédé de visualisation de microvasculature tissulaire à l'aide d'ultrasons
WO2020223679A1 (fr) * 2019-05-02 2020-11-05 The Board Of Trustees Of The Leland Stanford Junior University Quantification de cartes paramétriques d'ultrason à contraste amélioré au moyen d'une analyse basée sur la radiomique
US10846861B2 (en) * 2018-08-29 2020-11-24 Hitachi, Ltd. Image processor, image processing method, program for image processing, and magnetic resonance imaging apparatus
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Publication number Priority date Publication date Assignee Title
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US12614292B2 (en) 2014-04-25 2026-04-28 Thornhill Scientific Inc. Imaging abnormalities in vascular response
US11880989B2 (en) 2014-04-25 2024-01-23 Thornhill Scientific Inc. Imaging abnormalities in vascular response
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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060161062A1 (en) * 2003-06-12 2006-07-20 Bracco Research Sa Blood flow estimates through replenishment curve fitting in ultrasound contrast imaging

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7069068B1 (en) * 1999-03-26 2006-06-27 Oestergaard Leif Method for determining haemodynamic indices by use of tomographic data
EP1833373B1 (fr) * 2004-12-23 2015-12-16 Bracco Suisse SA Système et méthode d'évaluation de la perfusion en utilisant l'administration d'un bolus

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060161062A1 (en) * 2003-06-12 2006-07-20 Bracco Research Sa Blood flow estimates through replenishment curve fitting in ultrasound contrast imaging

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
Miyauchi et al., "Diffusion and Back-Flow Models for Two-Phase Axial Dispersion", Ind. Eng. Chem. Fundamen., 1963, 2 (4), pp 304-310. *
Tsoukias et al., "A computational model of oxygen delivery by hemoglobin-based oxygen carriers in three-dimensional microvascular networks", Journal of Theor Biol. 2007, October 21; 248(4): 657-674. *

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WO2017146886A1 (fr) * 2016-02-23 2017-08-31 Mayo Foundation For Medical Education And Research Imagerie du débit sanguin par ultrasons
US11457890B2 (en) 2016-02-23 2022-10-04 Mayo Foundation For Medical Education And Research Ultrasound blood flow imaging
US11006924B2 (en) 2017-03-24 2021-05-18 BURL Concepts, Inc. Portable ultrasound device
US12376827B2 (en) 2017-03-24 2025-08-05 BURL Concepts, Inc. Portable ultrasound device
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JP2020520711A (ja) * 2017-05-19 2020-07-16 メイヨ フオンデーシヨン フオー メデイカル エジユケーシヨン アンド リサーチ 超音波を用いた組織微小脈管構造の可視化のためのシステム及び方法
WO2018213839A3 (fr) * 2017-05-19 2018-12-27 Mayo Foundation For Medical Education And Research Système et procédé de visualisation de microvasculature tissulaire à l'aide d'ultrasons
JP7360522B2 (ja) 2017-05-19 2023-10-12 メイヨ フオンデーシヨン フオー メデイカル エジユケーシヨン アンド リサーチ 超音波を用いた組織微小脈管構造の可視化のためのシステム及び方法
US11213278B2 (en) 2017-05-19 2022-01-04 Mayo Foundation For Medical Education And Research System and method for visualization of tissue microvascular using ultrasound
JP7139357B2 (ja) 2017-05-19 2022-09-20 メイヨ フオンデーシヨン フオー メデイカル エジユケーシヨン アンド リサーチ 超音波を用いた組織微小脈管構造の可視化のためのシステム及び方法
JP2022172303A (ja) * 2017-05-19 2022-11-15 メイヨ フオンデーシヨン フオー メデイカル エジユケーシヨン アンド リサーチ 超音波を用いた組織微小脈管構造の可視化のためのシステム及び方法
US11684345B2 (en) 2017-05-19 2023-06-27 Mayo Foundation For Medical Education And Research System and method for visualization of tissue microvasculature using ultrasound
US10846861B2 (en) * 2018-08-29 2020-11-24 Hitachi, Ltd. Image processor, image processing method, program for image processing, and magnetic resonance imaging apparatus
US11654635B2 (en) 2019-04-18 2023-05-23 The Research Foundation For Suny Enhanced non-destructive testing in directed energy material processing
WO2020223679A1 (fr) * 2019-05-02 2020-11-05 The Board Of Trustees Of The Leland Stanford Junior University Quantification de cartes paramétriques d'ultrason à contraste amélioré au moyen d'une analyse basée sur la radiomique
US20240099585A1 (en) * 2020-12-18 2024-03-28 Lightlab Imaging, Inc. Flow Measurement Through OCT
US12495971B2 (en) * 2020-12-18 2025-12-16 Lightlab Imaging, Inc. Flow measurement through OCT
US20230414786A1 (en) * 2022-04-19 2023-12-28 Board Of Regents, The University Of Texas System Perfusion-guided gene therapy for improving cancer treatment
CN119786058A (zh) * 2024-12-09 2025-04-08 流域(广州)医疗科技有限公司 一种肺部icg荧光动态扩散定量分析方法
CN119679449A (zh) * 2025-02-24 2025-03-25 上海德济医院有限公司 动态监测下肢静脉血流状态的监测方法、系统及储存介质

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